Dr Kenneth Shain: Adding Monoclonal Antibody to Treatment Provides Depth of Response in Transplant-Eligible Newly Diagnosed MM

For patients with newly diagnosed multiple myeloma, treatment options are transitioning from 2- to 3-drug combinations in the transplant-ineligible population and from 3- to 4-drug combinations in the transplant-eligible population, said Kenneth Shain, MD, PhD, associate member of the Departments of Malignant Hematology and Chemical Biology and Molecular Medicine, and codirector of the Pentecost Myeloma Research Center, H. Lee Moffitt Cancer Center.

In an interview with The American Journal of Managed Care® (AJMC®), Shain outlined the trial data around adding a CD38 monoclonal antibody—daratumumab or isatuxumab—to the standard 3-drug therapy.

In part 1 of this interview, Shain discussed treatment for transplant-ineligible patients.

AJMC: Switching over to transplant-eligible patients, what are the current preferred triplet or quadruplet standards of care?

Shain: Like we talked about with the transplant-ineligible patients, treatment options are in a transition where we're moving from 3-drug therapies being a standard of care to 4-drug therapies. Some of those 3-drug therapies have nice phase 3 data. Bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) and carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd) are the 2 major 3-drug therapies that we use. I think we all learned that in some specialized cases—maybe acute renal failure and things of that nature—there may be a need for cyclophosphamide for a period of time before changing to an immunomodulatory drug (IMiD)–based therapy with that proteasome inhibitor (PI). That's been a standard of care for some time now. But I think there's really a lot of data and a lot of very strong data that's been coming out for the last few years, showing that 4 drugs—the addition of a CD38 monoclonal antibody to those 3-drug backbones—really adds a depth of response. Again, continued monoclonal antibody therapy adds long-term control of disease. So, those are all things that are very positive. We're learning now from the PERSEUS study¹ and the IsKia study² that there will probably be greater benefits in these larger randomized studies that are confirming these earlier phase studies.

We've moved in our institution from a 3-drug to a 4-drug regimen. What is the 4-drug regimen upfront? I think, we're going to continue to learn and identify patients who might fit one state versus another. The options for these 4-drug therapies are monoclonal antibodies: daratumumab (Dara), which has been studied the most to date, and then isatuximab, another CD38 with more data coming out where we're seeing some nice success with depth of response and things of that nature in the combination. The PIs are bortezomib versus carfilzomib. Lenalidomide and dexamethasone are the base for those other drugs. There's no comparative data of which 4-drug combination is better, but, institutionally, you have one that you probably prioritize over the other for certain subgroups. In our institution, it's mostly going to be Dara-VRd, because of the studies we participated in.

Overall, there may be some data suggesting that for high-risk patients, carfilzomib might be nice to have in there. Isatuximab, again, has some really nice data² that came out of the American Society of Hematology meeting in 2023 suggesting really deep, deep, deep levels of response and MRD negative rates when you use isatuximab with KRd. These are all things we're learning, but really it should be that standard of care is a 3-drug regimen for induction therapy followed by transplant, and transplant means high-dose melphalan plus autologous stem cell rescue—it's not really transplant, it's the rescue with your own stem cells. Then all of that followed by lenalidomide maintenance or response-/risk-adapted maintenance therapy. So again, high-risk patients need to have a doublet, usually a PI and an IMiD, for their maintenance therapy.

We’re still learning about what the induction therapy is, but it has moved from 3 drugs to 4 drugs, and the addition is really a monoclonal antibody CD38. But there is no data telling you which one's the right one to add, which PI is better than the other. These are all things that, really, we don't know answers to. So, again, it comes down to the patient. What do they walk in the door with? Do they have cardiovascular issues? It might push you to one PI versus another. Do they have neuropathy issues from diabetes? It pushes you to one PI or the other. These are the things you have to debate and decide.

AJMC: What key trial data has supported the adoption of these regimens?

Shain: The 3-drug therapy to transplant to maintenance therapy really was driven a lot by earlier studies. The IFM³ studies are ones that looked at 3-drug therapy, VRd or RVd, with or without transplant, then lenalidomide maintenance. These are the studies that raised the question of transplant to establish how well you can do with that sequence of therapy with or without the transplant.

Then building on that, we had studies looking at KRd. The MANHATTAN study⁴ showed you can get deep levels of response in early phase studies and establishing KRd. Then the ENDURANCE study⁵ comes around, and we thought we would be able to figure out the difference between KRd and RVd. But really what we learned is that in the end, they weren't that different, you were just treating side effects. Maybe there is a little more depth of response with carfilzomib in KRd, but again, the progression-free survival (PFS) or disease control was pretty similar.

For the 4-drug therapies, there's a whole slew of trial data coming out. I think there were 2 that pushed our decision making the most. The GRIFFIN trial⁶ was looking at Dara-RVd versus RVd and transplant. There was some consolidation therapy for 2 cycles after transplant with those same 4 versus 3 drugs, and then continued therapy or maintenance with 2 drugs versus 1 drug. By adding that monoclonal antibody, you're gaining efficacy all the way without adding a lot of toxicity. That was a phase 2 randomized controlled trial, so it was small, but it really showed us we can do better, we can get better responses. So, it really drove a lot of the 3- to 4-drug transition.

Then the PERSEUS study really solidified that. We're getting the final numbers now and it was just published in January in the New England Journal of Medicine. The results highlighted that yes, 4 drugs versus 3 drugs all the way through will provide a benefit in terms of depth of response and PFS, the study end point. And maybe we'll see some other good outcomes as we go along.

I think the MASTER study⁷ is one of my favorite studies, because it really analyses a 4-drug regimen—Dara-KRd—followed by transplant and additional treatment with the 4-drug regimen, and then it uses a response-adapted approach to design to determine what we're going to do for therapy afterwards. So, if the patient was MRD negative, meaning we can't measure disease down to less than 100,000 cells at 2 time points, we're going to stop therapy and monitor. We've learned that in some patients—we're not doing this as standard of care—we might be able to stop therapy if they achieve a certain level of response. That study really kind of highlighted, to me, that if you can get really deep levels of response, high levels of what's called MRD negativity, there may be a way to study stopping therapy in a randomized fashion for certain patient populations. And there may be certain patient populations that probably need therapy no matter what, and these are the high-risk patients. They are defined by what we call double-hit, where they can contain 2 molecular features of high risk.

There have been other studies looking at 4-drug combinations that are giving a similar outcome, but I think those are the ones that drive most of what we do in the United States. My lab is also participating in a study looking at 3 versus 4 drugs and the concept of MRD-driven treatment: if you achieve MRD negativity, can we delay the need for transplant and just go right to maintenance therapy? That study is ongoing right now. The ADVANCE study⁸ is a multi-institutional study looking at Dara-KRd versus KRd, and then do you do transplant or not if you achieve the right response? I think that’s the next phase, to really start using things to dictate what to do with our patients and how to stop or start or change their maintenance or maybe avoid potentially highly toxic therapies—very good but highly toxic therapies—in certain individuals.

AJMC: How do you differentiate between triplet versus quadruplet regimens for transplant-eligible patients now, and what efficacy and safety considerations guide this choice?

Shain: This is the safety versus efficacy concern. A patient walks in to see me and they're transplant eligible, fitness goes into the equation without question, but most of the time when you're transplant eligible, the fitness can be dictated by the disease, not by the person. The disease has done something that makes them less fit for now. We still want to be aggressive in how we take care of the disease. We want to get responses as quickly as we can and as low as we can. When someone walks in to see me, most of the time, we're going to do 4-drug therapy. Dara-VRd versus Dara-KRd are the 2 we're going to pick from. Three-drug therapies are really for patients who have specific comorbidities—for instance, neuropathy and heart issues. But for the most part, we're going to use 4 drugs. We might have to attenuate the dosing a little bit to make it safer for the patients.

The differences between which PI—bortezomib versus carfilzomib—again, comes down to: what are they walking in with? Do they have a lot of neuropathy? Do they have a history of cardiovascular issues? Neuropathy may make us move away from bortezomib, while cardiovascular issues or uncontrolled hypertension might make us move away from carfilzomib. I’m not saying that you can't use either, but that's where you want to kind of think about it. I think the data is still a little more challenging when it comes to which monoclonal antibody, if there's a choice, is better for certain individuals. Right now, dosing is one way to think about it. One is delivered subcutaneously and one is faster and spreads out to monthly dosing. So these are all things that can make one more attractive than the other. There's evolving data: maybe there's a high-risk signal that might be overcome or at least a little better in terms of depth of response for that isatuximab, carfilzomib, lenalidomide, and dexamethasone group. Again, these have not been tested head-to-head, but those are really intriguing questions that are out there.

In my world, it's mostly going to be 4 drugs. I would prefer reducing the doses of some of the drugs versus leaving some out for these transplant-eligible patients. I really think that getting them to the deepest response possible is appropriate, getting them transplanted, giving them high-dose therapy with the lowest-burden disease, all trying to drive to that MRD-negative status is a really important part of how we take care of patients today.

References

1.Sonneveld P, Dimopoulos MA, Boccadoro M, et al; PERSEUS Trial Investigators. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054

2. Gay F, Roeloffzen W, Dimopoulos MA, et al. Results of the phase III randomized Iskia trial: isatuximab-carfilzomib-lenalidomide-dexamethasone vs carfilzomib-lenalidomide-dexamethasone as pre-transplant induction and post-transplant consolidation in newly diagnosed multiple myeloma patients. Blood. 2023;142:(Supp 1):4. doi:10.1182/blood-2023-177546

3. Attal M, Lauwers-Cances V, Hulin C, et al; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750

4. Landgren O, Hultcrantz M, Diamond B, et al. Safety and effectiveness of weekly carfilzomib, lenalidomide, dexamethasone, and daratumumab combination therapy for patients with newly diagnosed multiple myeloma: the MANHATTAN nonrandomized clinical trial. JAMA Oncol. 2021;7(6):862-868. doi:10.1001/jamaoncol.2021.0611

5. Kumar SJ, Jacobus SJ, Cohen AD, et al. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (E1A11): a multicenter, open label, phase 3, randomized, controlled trial. Lancet Oncol. 2020;21(10):1317-1330. doi:10.1016/S1470-2045(20)30452-6

6. Voorhees PM, Sborov DW, Laubach J, et al. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol. 2023;10(10):e825-e837. doi:10.1016/S2352-3026(23)00217-X

7. Costa LJ, Chhabra S, Medvedova E, et al. Minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma (MASTER): final report of the multicentre, single-arm, phase 2 trial. Lancet Haematol. 2023;10(11):e890-e901. doi:10.1016/S2352-3026(23)00236-3

8. Landgren O, Maura F, Kazandjian D. Advance multicenter dlinical trial: MRD-driven therapy in newly diagnosed multiple myeloma patients. Blood. 2023;142(Supp 1):3392. doi:10.1182/blood-2023-186834